Alcohol-free transdermal insulin composition

ABSTRACT

The instant invention is directed toward a dermal delivery system composition comprising an aqueous base vehicle including Emu oil, at least one fatty acid alkyl ester, polyethylene glycol, and a gelling agent, in combination with a therapeutically effective amount of at least one species of insulin, and to processes for the manufacture and use thereof.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. patent applicationSer. No. 10/412,637, filed Apr. 11, 2003 now U.S. Pat. No. 7,033,998,the contents of which are herein incorporated by reference.

FIELD OF THE INVENTION

This invention relates to an insulin composition in combination with analcohol-free dermal delivery system for transdermal application and toprocesses for manufacture and use thereof.

BACKGROUND OF THE INVENTION

Insulin is a naturally occurring hormone secreted by the beta cells ofthe islands of Langerhans in the pancreas in response to increasedlevels of glucose in the blood. The hormone acts to regulate themetabolism of glucose and the processes associated with the intermediarymetabolism of fat, carbohydrates and proteins. Insulin lowers bloodglucose levels and promotes transport and entry of glucose into musclecells and other tissues. Due to the chemical nature of insulinmolecules, the traditional route of insulin administration in diabeticpatients, who require multiple daily doses of insulin, is intradermal orsubdermal injection.

Prior art efforts to develop a non-injectable transdermal insulindelivery system for the treatment of diabetes have not been successfulto date. While insulin can be systemically delivered to a patient by thetopical application of an insulin-containing vehicle, the systemic bloodlevels of insulin that are achievable using this delivery method haveproven to be generally inadequate for meeting the demands of thediabetic patient.

Various methods have been developed for enhancing the transdermaldelivery of insulin including improved passive diffusion carriers forincreasing the permeability of the epidermis, sonophoresis,iontophoresis and ionosonic transport. Passive diffusion through theouter layer of skin has been used successfully for the delivery of lowmolecular weight lipophilic drugs such as scopolamine, estradiol andnitroglycerine, but has been largely unsuccessful for the transdermaldelivery of hydrophilic peptides such as insulin due to the low skinpermeability of such peptides. Thus, mechanical vibrational energyand/or iontophoresis are employed to increase skin permeability andfacilitate transdermal insulin delivery. Sibalis et al., in U.S. Pat.No. 4,940,456, teaches an apparatus and method for the iontophoreticallymediated transdermal delivery of insulin. Henley, in U.S. Pat. Nos.5,667,487 and 5,658,247 discloses an ionosonic apparatus suitable forthe ultrasonic-iontophoretically mediated transport of therapeuticagents across the skin. Insulin has a tendency to form dimers andhexamers in pharmacological compositions, which are considered to be toolarge for transdermal delivery. Brange, in U.S. Pat. No. 5,597,796,suggests chemically modifying insulin to produce insulin analogs thatresist intermolecular association and enable improved iontophoreticdelivery. Jang et al., in U.S. Pat. No. 5,681,580, discloses a patchcontaining insulin formulated in a gel for the iontophoretically driventransdermal delivery of insulin. Notwithstanding the advances in methodsfor the transdermal delivery of insulin described above, the transdermaldelivery of insulin in a quantity sufficient to attain a therapeuticlevel in the blood of diabetic patients has heretofore not beenpossible.

Clinical use of transdermal drug delivery has been limited because veryfew drugs are able, at least by passive diffusion alone, to penetratethe skin at a sufficient rate to produce a useful systemic drugconcentration in the patient. The outer layer of the skin, the stratumcorneum, is a major barrier to diffusion of low and especially highmolecular weight drugs across the skin to the bloodstream. One drug forwhich an effective transdermal delivery system has long been sought isinsulin, a therapeutic agent useful in the control of both Type I(juvenile onset) and Type II (adult onset) diabetes. Insulin,unfortunately, constitutes an example of molecules which do not readilydiffuse through the stratum corneum at a therapeutically useful rate.

While there have been attempts in the prior art to develop transdermal“patches” which contain a particular amount of insulin, which may betransferred at a particular rate, these patches have numerouslimitations. One specific limitation is that insulin users must oftengauge their requirements relative to physical activity and ingestion ofcarbohydrates. Additionally, there are different types of insulin, e.g.long-acting and short-acting, and the patient must develop skill inblending both the type and quantity of insulin in order to adequatelycontrol their blood sugar levels. The use of multiple patches havingvariable dosage strengths and insulin response characteristics thusbecomes problematic.

Thus there remains a longfelt need for a dermal delivery system forinsulin in a convenient format, e.g. a gel or cream, which can beformulated with insulin compounds having varied release characteristics,and whereby the dosage could be determined as a function of the volumeapplied.

DESCRIPTION OF THE PRIOR ART

U.S. Pat. No. 6,416,772 teaches a topical dermal anesthetic compositionfor relief of pain comprising alcohol in an amount by weight of about 57to about 91 percent; glycerin in an amount by weight of about 1 to about12 percent; an analgesic agent in an amount by weight of about 2 toabout 28 percent, the analgesic agent comprising a derivative ofsalicylic acid; methylsulfonylmethane (MSM) in an amount by weight ofabout 0.02 to 5 percent; and Emu oil in an amount by weight of about0.01 to 3 percent. The composition provides transdermal pain when theanalgesic agent is applied directly to an area of pain.

Alcohol, preferably ethyl or isopropyl alcohol, is taught as beingnecessary to effectively dissolve the analgesic so that it can beabsorbed through the skin. Glycerin, in turn, is required to act as astabilizer for the acetylsalicylic acid, triethanolamine salicylate, orother analgesic agent, such that the alcohol does not significantlyaffect the marketable shelf life of the composition. Glycerin is alsotaught as being necessary to sufficiently disperse the analgesic agentsuch that the composition does not need to be shaken or stirred beforetopical use. Methylsulfonylmethane (MSM) and Emu oil are taught as beingincluded to help facilitate the absorption of the composition into theskin and also, due to the pain relieving characteristics in and ofthemselves, potentiate the analgesic to increase the efficacy of thecomposition.

This patent fails to teach a composition which is effective inalleviating pain when applied to various trigger points, distal from theactual perceived area of discomfort. Furthermore, the '772 patentrequires the use of alcohol for transdermal delivery, which causesdegradation of the analgesic, and subsequently requires glycerin as astabilizer to retard the alcohol degradation.

U.S. Pat. No. 6,346,278 teaches a lipid extract of Perna canaliculus orMytilus edulis as an active component, in a composition suitable fortransdermal administration comprising an ointment or lotion base orvehicle, which may include a skin penetration enhancing agent to assistin administration of the active component. Suitable bases or vehiclesare oils such as olive or Emu oil, administered alone or with apenetrant such as cineole or limonene.

U.S. Pat. No. 6,444,234 teaches an alcohol containing pharmaceuticalcompositions for the transdermal administration of a medicament or otheractive agent by topical application of the composition to the skin ofhumans or other animals. Methodology for formulating such compositionswhich provide for very rapid uptake of the medicament and transmigrationinto and through the skin to either fatty tissues or the vascularsystem, while minimizing irritation to the skin and/or immunologicalresponse, is based on a transdermal delivery system (TDS) wherein themedicament is modified to form a true solution in a complex formed fromparticular solvents and solvent and solute modifiers in combination withskin stabilizers. Analgesics such as ibuprofen and the like, MSM and Emuoil are taught as useful in combination with the transdermal deliverysystem.

U.S. Pat. No. 6,528,040 teaches an Emu oil-based formulation for use asan analgesic, anesthetic and antipruritic. The formulation contains 0.01to 13 wt % alkyl esters; and 20 to 70 wt % Emu oil; 10 to 33 wt % benzylalcohol; 10 to 33 wt % benzoin; 0.2 to 2 wt % allantoin; 0.25 to 1.25 wt% methylparaben and 0.01 to 0.30 wt % propylparaben. The formulation maybe formulated as a spray or transdermal formula and may be used fortreatment of chronic cutaneous ulcers and burn wounds.

U.S. Pat. No. 5,885,597 teaches a topical composition for relieving painin a person in need of such relief, consisting essentially of aneffective amount of a combination of at least one corticoid analgesic,at least one arylpropionic acid type analgesic, and at least onep-aminobenzoic acid ester type local anesthetic; an amount effective inenhancing the effectiveness in relieving pain of the combination ofcapsaicin, and an amount effective to increase the transmission thereofthrough the skin of at least one phospholipid and at least onepolyoxyethylenepolyoxypropylene copolymer.

U.S. Patent Application 20030031724 teaches compositions that may becost-effectively derived or processed from the Emu, Dromiceiusnovaehollandiae, and used as anti-inflammatory agents in patients. Theapplication does not contemplate the use of MSM or insulin compositionsin a transdermal delivery environment.

U.S. Patent Application 20010033838 teaches the use of Emu oil and itsvarious fractions as a carrier for antifungal, antibacterial, andantiviral medications and preparations. The use of MSM in combinationwith Emu oil is taught, however when transdermal application is desiredthe Emu oil is replaced with a liposomal or oil-based transdermalcomponent.

U.S. Pat. No. 6,024,975 is directed toward a high molecular weight drugwhich is transdermally administered by applying a polymer skin enhancerand a drug active to the skin of the patient. The drug may beencapsulated or the drug solution may be partly encapsulated and partlyfree. The skin enhancer which is required is polyvinylpyrrolidone(PVP)and it is mixed at between 7 and 35% of the drug. A gelling agentmay be optionally added at up to 20% by volume. The chemical system ispreferably administered via a multidose transdermal drug patch assemblywhich includes a drug-impervious support impressed to form a series ofcompartments. Each compartment is a reservoir for a unit dose of anactive drug designed to be transdermally administered. The support isadhesively secured to the skin of a patient. Individual devices areprovided for resealably enclosing the drug in each of the reservoirs.The individual enclosing devices are removable to release the unit doseinto contact with the skin of the patient and are actuable to controlthe transdermal absorption of the drug actives. The patent disclosure islargely directed toward trans-dermal medication assemblies and moreparticularly to such assemblies consisting of multiple unit-dosereservoirs with each reservoir having individual tear and releaseresealable closure means for initiation and administration of themedication. However, it is suggested that the drug may also beadministered in a creme. All formulations would nevertheless requirepolyvinylpyrrolidone.

U.S. Pat No. 6,444,240 is directed toward compositions containinginsulin formulated for topical application and a method for using thecompositions for the cosmetic treatment of wrinkles.

SUMMARY OF THE INVENTION

The instant invention discloses a dermal delivery system compositioncomprising an aqueous base vehicle including at least one fatty acidalkyl ester having thirteen to thirty six carbon atoms, polyethyleneglycol-8 (PEG-8), Emu oil, and a gelling agent. For enhanced skinpenetration methylsulfonylmethane (MSM) may be added to the composition.One or more active insulin ingredients are added to this aqueous basevehicle.

Examples of suitable fatty acid alkyl esters include, albeit not limitedto, methyl laurate, methyl myristate, methyl palmitate, methyl stearate,methyl behenate, ethyl oleate, ethyl linoleate, butyl oleate, butylstearate, isopropyl myristate, isopropyl palmitate, dodecyl acetate,tetradecyl octanote, cetyl palmitate, and stearyl stearate.

The aforementioned fatty acid alkyl esters facilitate compounding andcan be added to the formulation from about 0.001 to about 31.0 wt % ofthe composition, preferably about 3 wt %.

Examples of idoneous gelling/emulsifying agents that can be used in thepresent invention include guar gums, xanthan gums, carrageenan,cellulose, hydroxyalkyl celluloses, sodium carboxycelluloses, SEPIGEL305, gelatin, agar, starch, or the like. SEPIGEL 305 is a trademark andmanufactured by Seppic (Fairfield, N.J.). SEPIGEL 305 is agelling/emulsifying agent comprising about 40% polyacrylamide, about 15%C₁₃-C₁₄ Isoparaffin and about 5% laureth-7, and q.s. water.

The gelling/emulsifying agent is added to the formulation to achieve thedesired viscosity and can range from about 0.001 to about 31.0 wt %,preferably about 3 wt %.

The preferred polyethylene glycol used herein is PEG-8 (tradenamePROTACHEM 400, manufacture by Protameen Chemical, Inc. Totawa, N.J.) andcan be added to the formulation in amounts from about 0.001 to about31.0 wt % of the composition, preferably about 3 wt %. Emu oil is addedto the formulation to facilitate the absorption of the composition intothe skin. Emu oil can be added to the instant formulation in amountsfrom about 0.001 to about 31.0 wt %.

In a preferred embodiment, the instant invention discloses a dermaldelivery system composition comprising an aqueous base vehicle includingEmu oil (American), isopropyl palmitate (tradename PROTACHEM IPP, soldby Protameen Chemical, Inc. Totawa, N.J.), PEG-8, and SEPIGEL 305 (soldby Seppic). Methylsulfonylmethane (MSM) may also be included to helpfacilitate the absorption of the composition into the skin.

To this base vehicle, one or more active insulin ingredients are added,e.g. HUMALOG.

As opposed to the use of injected insulin, topical creams of the instantinvention have the advantage of not requiring the patient or a caregiverto give an injection; nor must the patient carry and/or transport thenecessary paraphernalia required for giving an injection.

The dermal delivery system, as illustrated herein, is alcohol free andtherefore does not suffer from the problems of decreased shelf-lifeassociated with alcohol containing prior art formulations. Since alcoholis not utilized, the presence of glycerin is likewise not required.Thus, a unique alcohol-free dermal delivery system is provided whichprovides enhanced penetration via the dermal layers thereby enabling asafer, quick-acting, and easier-to-comply alternative to capsules andtablets.

Accordingly, it is an objective of the instant invention to provide analcohol-free, cream base rapid dermal delivery system for transdermaldosing of insulin compositions effective for the therapeutic treatmentof diabetes.

It is another objective of the instant invention to provide a processfor manufacture of said dermal delivery system.

Other objects and advantages of this invention will become apparent fromthe following description taken in conjunction with the accompanyingdrawings wherein are set forth, by way of illustration and example,certain embodiments of this invention.

DETAILED DESCRIPTION OF THE INVENTION

In order to reduce to practice a dermal delivery system which providesenhanced skin penetration, it is necessary to understand the parameterswhich affect this phenomenon.

Various Factors Affecting Skin Penetration:

1) Oil solubility (J Pharm Sci “Linear relationships between lipophiliccharacter and biological activity of drugs.” 1972 Jan;61(1):1-19) themore oil soluble [lipophilic] the substance, the greater the skinpenetration;

2) Molecular weight (the smaller the molecule, the easier penetration);

3) Creams, gels and liquids penetrate better than solids;

4) Penetration enhancers improve topical absorption of lipophilicsubstances (Targeted drug delivery to the skin and deeper tissues: roleof physiology, solute structure and disease; Clin Exp Pharmacol Physiol1997 Nov;24(11):874-9).

EXAMPLE 1

A non-limiting illustrative example is presented herein; the followingis only an example and not solely representative of the inventiveconcepts discussed herein.

In accordance with a preferred embodiment of the instant invention,ingredients for a vehicle base had the following components.

Component Amount (wt %) American Emu Oil ~3% Isopropyl Palmitate ~3%PEG-8 ~4% SEPIGEL 305  ~3%* Methylsulfonylmethane ~0.75%   Water (DI)q.s (*additional in 1% increments, if needed for gelling)Formulation Procedure:

In order to produce the transdermal insulin delivery system/compositionas set forth above, the following procedure was performed:

-   -   1. Weigh out active ingredients, incorporating about 1 unit of        HUMALOG insulin per 1 gram cream;    -   2. Measure about 3% American Emu oil into high speed mixing        apparatus;    -   3. Add active ingredients to Emu oil. Mix until all powder is        incorporated into oil. Mixture will be very dry;    -   4. Measure isopropyl palmitate and PEG-8, add to Emu mixture;    -   5. Let mix for ½ hour;    -   6. Add DI water, mix for 5 minutes, scraping sides of mixing        container occasionally;    -   7. Add about 3% SEPIGEL 305, let incorporate for 5 minutes; If        desired consistency has not been achieved, add SEPIGEL 305 in 1%        increments until desired consistency is achieved.        In order to produce a transdermal insulin delivery        system/composition the above procedure was followed and the        subsequent tests were performed to establish efficacy of the        transdermal delivery system.        Application of Transdermal Cream with Insulin in Measured Dose    -   1. Measure off about 1 gram of mixture;    -   2. Apply to inside of wrist and rub in until skin feels dry;    -   3. Take glucose levels every ten minutes and record the        readings;    -   4. Glucose levels dropped below 50 within 30 to 40 minutes;    -   5. Ingested 2 glucose tablets and 2 Hershey bars to stop sugar        level drop;    -   6. This study was repeated on 3 different occasions thereby        demonstrating that the insulin transdermally entered the        circulatory system in therapeutically effective quantities        thereby affecting a change in sugar levels in the body.

In accordance with this invention, an insulin composition is understoodto mean any type of insulin useful in the therapeutic treatment ofdiabetes, used singly, or in any combination, in order to provide anydesired affects. Such compositions are illustrated by, albeit notlimited to various species of insulin, such as a blend of short actinginsulin; long acting insulin; insulins which provide a base levelconcentration for a prolonged period and which can be supplemented witha second formulation for providing short acting control, and variouscombinations thereof.

All patents and publications mentioned in this specification areindicative of the levels of those skilled in the art to which theinvention pertains. All patents and publications are herein incorporatedby reference to the same extent as if each individual publication wasspecifically and individually indicated to be incorporated by reference.

It is to be understood that while a certain form of the invention isillustrated, it is not to be limited to the specific form or arrangementof parts herein described and shown. It will be apparent to thoseskilled in the art that various changes may be made without departingfrom the scope of the invention and the invention is not to beconsidered limited to what is shown and described in the specification.

One skilled in the art will readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. Anycompounds, methods, procedures and techniques described herein arepresently representative of the preferred embodiments, are intended tobe exemplary and are not intended as limitations on the scope. Changestherein and other uses will occur to those skilled in the art which areencompassed within the spirit of the invention and are defined by thescope of the appended claims. Although the invention has been describedin connection with specific preferred embodiments, it should beunderstood that the invention as claimed should not be unduly limited tosuch specific embodiments. Indeed, various modifications of thedescribed modes for carrying out the invention which are obvious tothose skilled in the art are intended to be within the scope of thefollowing claims.

1. An alcohol-free composition effective for transdermal delivery ofinsulin comprising in combination: an effective amount of Emu Oil, aneffective amount of at least one fatty acid alkyl ester, an effectiveamount of polyethylene glycol, a gelling agent in an amount effectivefor gelling, a therapeutically effective amount of insulin, and sterilewater sufficient to make 100% W/W.
 2. The composition for transdermaldelivery of insulin as set forth in claim 1, wherein said fatty acidalkyl ester comprises at least one member selected from the groupconsisting of methyl laurate, methyl myristate, methyl palmitate, methylstearate, methyl behenate, ethyl oleate, ethyl linoleate, butyl oleate,butyl stearate, isopropyl myristate, isopropyl palmitate, dodecylacetate, tetradecyl octanote, cetyl palmitate, and stearyl stearate. 3.The composition for transdermal delivery of insulin as set forth claim1, wherein said gelling agent comprises at least one member selectedfrom the group consisting of guar gums, xanthan gums, carrageenan,cellulose, hydroxyalkyl celluloses, sodium carboxycelluloses, gellingagent including a combination of about 40% polyacrylamide, about 15%C₁₃-C₁₄ iso-paraffin, about 5% laureth-7 and water in an amountsufficient to make 100% W/W gelatin, agar, starch, or the like.
 4. Thecomposition for transdermal delivery of insulin as set forth in claim 1,wherein said polyethylene glycol is polyethylene glycol-8.
 5. Thecomposition for transdermal delivery of insulin as set forth in claim 1,further comprising an effective amount of methylsulfonylmethane.
 6. Analcohol-free insulin composition effective for transdermal deliveryformulated by a method comprising: providing a therapeutically effectiveamount of insulin; providing an effective amount of Emu oil in a highspeed mixing apparatus; adding said insulin to said Emu oil and mixinguntil a homogeneously blended composition is formed; adding an effectiveamount of at least one fatty acid alkyl ester and an effective amount ofpolyethylene glycol to said homogeneous blend, and mixing for asufficient amount of time; adding an effective amount of at least onegelling agent to achieve homogeneity and a gel-like consistency afterblending; and adding additional gelling agent, if necessary, untildesired gel consistency is achieved; adding sterile water sufficient tomake 100% W/W and mixing to homogeneity: whereby said alcohol-freeinsulin composition effective for transdermal delivery is produced.